Dr Sunny Kaul shares some key points for primary management of patients with COPD and common comorbidities
Read this article to learn more about:
- common non-pulmonary comorbidities associated with COPD
- diagnosis, assessment, and management of the most common extrapulmonary comorbidities.
Chronic obstructive pulmonary disease (COPD) is associated with various non-pulmonary comorbidities, including those listed in Box 1, below.1 Their prevalence varies depending on the patient population, methods of evaluation, and disease definition; however, the age-, sex-, and smoking-adjusted frequency is greater than expected in patients with COPD independent of the variations in prevalence.
Box 1: Comorbidities commonly associated with COPD
- Cardiovascular disease:
- atrial fibrillation
- cerebrovascular accident
- ischaemic heart disease
- heart failure
- right-sided heart failure
- Gastro-oesophageal reflux disease
- Low bone mineral density and osteoporosis
- Lung cancer
- Skeletal muscle dysfunction.
Comorbidities have a significant impact on the health status, use of healthcare services, and mortality in patients with COPD, who have, on average, ≥4 additional diseases2,3 with one-third of patients with COPD using 5–10 different medications on any given day.3,4 As each comorbidity needs to be diagnosed, assessed, and managed appropriately to optimise patient outcomes, this article focuses on management of some of the most common extrapulmonary comorbidities.
1 Ischaemic heart disease
The prevalence of ischaemic heart disease (IHD) in patients with COPD is high.5 The two conditions share symptoms, which can make it difficult for clinicians to differentiate and quantify the relationship between them; targeted investigations are therefore required, for example, transthoracic echocardiography (TTE) and 12-lead electrocardiogram (ECG).6 Management includes smoking cessation, optimal management of other conditions that predispose to atherosclerosis (e.g. hypertension and diabetes), and specific treatments for IHD.4,7,8,
Many clinicians are reluctant to prescribe beta blockers alongside the beta agonists used almost ubiquitously by patients with COPD, so less effective alternatives such as calcium-channel blockers are often employed as anti-anginal drugs; however, the cardioselective beta blockers atenolol and bisoprolol are well tolerated in COPD and should not be withheld,9,10 particularly given emerging evidence that they may also benefit patients with COPD outside of the context of cardiovascular disease.11 Concerns regarding an increased cardiovascular risk from drugs used to treat COPD are not supported by data from large trials, and appropriate bronchodilator therapy should therefore not be withheld.9,10
2 Heart failure
In the Evaluation of COPD longitudinally to identify predictive surrogate end-points (ECLIPSE) study, 7% of patients overall had heart failure (HF) and the prevalence increased with increasing airflow limitation.6,8,12 Furthermore, in one study, 39% of outpatients with HF had COPD, which is associated with shorter time to hospital admission and a substantially increased risk of death.13 Patients with diastolic dysfunction admitted for COPD exacerbations stay in hospital longer and have more exacerbations.14
Diagnosis of HF can be challenging in patients with COPD, due to the common symptomatic manifestation of breathlessness. Assessment should include a clinical history to identify symptoms of orthopnoea/ paroxysmal nocturnal dyspnoea, in addition to a full cardiovascular examination.6 Causes of heart failure may be identified using a TTE with features such as regional wall motion abnormalities, valvular disease, and left ventricular hypertrophy, and electrocardiography to identify arrhythmias. The following methods may also be useful in diagnosing HF in people with COPD:
- blood tests (for example, tests for NT pro-brain natriuretic peptide [NT-proBNP]) may be helpful in differentiating COPD from HF in the stable and acute settings6
- chest X-rays allow practitioners to measure the cardiothoracic ratio and look for peribronchial cuffing and Kerley B lines as signs of airway and interstitial oedema6
- magnetic resonance imaging (MRI), although expensive and not widely available, is the gold standard for accurate, non-invasive cardiac assessment6
Cardioselective beta blockers have been shown to be effective in patients with HF. They are well tolerated in patients with COPD and their use should be encouraged.6,11
3 Right-sided heart failure
Right ventricular dysfunction or cor pulmonale develops due to COPD-associated pulmonary hypertension (PH), which increases with increasing severity of disease, progresses slowly,6,15 and reduces survival.6,16
Transthoracic echocardiography is the first-line non-invasive investigation for secondary PH and cor pulmonale; however, a study has shown that in patients with advanced lung disease that remains invasive, right-side heart catheterisation is the gold standard; this is because TTE is prone to overestimate systolic pulmonary artery pressure (sPAP), which is impossible to measure in more than 50% of patients.6,17 Surrogate right ventricular parameters are also inaccurate compared with right heart catheterisation.17 Just over one-half of the patients with obstructive lung disease had an echocardiogramderived sPAP within 10 mmHg of the result determined by catheterisation.17
The best non-invasive imaging for right heart pathology is cardiac MRI; however, issues of cost and accessibility are often prohibitive.6
Treatment options for right heart failure include long-term oxygen therapy (LTOT) to slow progression of PH and loop diuretics to provide symptomatic relief from peripheral oedema.
The clinical usefulness of biomarkers such as NT-proBNP, of drugs that act on the angiotensin pathway, and of beta blockers in patients with cor pulmonale has not been fully elucidated.6
Cardiac arrhythmias are present in approximately 12–14% of patients with COPD.6,18
The prevalence of atrial fibrillation (AF) increases with disease severity and is linked to a higher frequency of exacerbations. The dyspnoea, eosinopenia, consolidation, acidaemia, and atrial fibrillation (DECAF) score19 can accurately predict in-hospital mortality in patients hospitalised with acute exacerbations of COPD.19
Concerns that chronic respiratory drugs (short-acting bronchodilators such as salbutamol and terbutaline) induce cardiac arrhythmia are not borne out by the evidence (except for sinus tachycardia).9 Management of COPD should not generally be altered for patients with AF.6 Cardioselective beta blockers should not be withheld if indicated for stable COPD, although the paucity of data means their safety in acute exacerbations is less clear.
5 Cerebrovascular disease
Fourteen percent of patients with COPD report a cerebrovascular event,4 and stroke is more common in patients with COPD than the general population (9.9% vs 3.2%, respectively).20 Chronic obstructive pulmonary disease is associated with a 2.8-fold higher incidence of acute stroke, and the risk of stroke is 1.3-fold higher in the first 7 weeks after an acute exacerbation.6,21 Common conditions that increase the risk of cerebrovascular disease (e.g. smoking, hypertension, hypercholesterolaemia, diabetes, AF, previous cerebrovascular accident/ transient ischaemic attack) should be identified and managed appropriately according to best practice. Carotid artery bruits should be sought in patients with COPD at risk of stroke, who should be investigated thoroughly. There is currently a surprising lack of data regarding patients with COPD and stroke.6
6 Low bone mineral density and fracture risk: osteoporosis
Prevalence of osteoporosis in patients with COPD ranges from 9% to 69%.22 Low bone mineral density (BMD) (T-score <−1) is present in 40–70% of patients with COPD and osteoporosis (T-score <−2.5 or existing fragility fracture) in 4–59%.23 Although low BMD is more common in women with COPD, men are also at high risk.6 Airflow obstruction is independently associated with reduced bone mineral density and the prevalence of osteoporosis increases as the severity of airflow obstruction increases.24,25
Low BMD is related to disease severity, CT-quantified emphysema score, arterial stiffness, systemic inflammatory markers, body mass index (BMI), and physical activity, and the risk of osteoporosis increases with decreasing forced expiratory volume in 1 second (FEV1).6,26 Fractures associated with osteopenia and osteoporosis can have a profound and dramatic impact on patient outcomes. Although fractures are more common with osteoporosis than osteopenia, most low-impact fractures occur with osteopenia,26 so it may be better to intervene at higher BMD scores than is the current practice.
Rib fractures may lead to reduced sputum airway clearance due to hypoventilation, which may contribute to exacerbations.23 Vertebral compression fractures can cause back pain and kyphosis, thereby impairing lung mechanics and contributing to a decline in pulmonary function;23 these fractures are a major concern, even when asymptomatic, as previous fractures are a risk factor for new vertebral and non-vertebral fractures.27
Hip fractures are the most important complication of osteoporosis in terms of quality of life, survival, and health economics.28,29 The exact prevalence/ relationship of osteoporotic hip fractures in COPD is unknown but a history of COPD is associated with a lower BMD at the spine and hip.26,30 Systemic steroids are used to treat COPD exacerbations despite their adverse effects on BMD and related fractures. There is a strong inverse correlation between BMD and total cumulative steroid dose and a significant correlation between daily dosage levels and fracture risk.31-33
Patients with COPD who take oral corticosteroids are more likely to experience one or more vertebral fractures.34
Detection and treatment of low BMD in patients with COPD is critical to minimise the risk of fractures. Tools such as FRAX® can identify patients with a high 10-year probability of bone fracture,35,37 who should then be screened with bone densitometry. All patients at risk of osteoporosis should also undergo radiography to identify vertebral compression fractures, measurement of 25-hydroxyvitamin D levels, and dual energy X-ray absorptiometry (DXA).37 Standard supplementation with vitamin D and calcium must be considered in all atrisk patients.37
Antiresorptive treatment should be started in patients with COPD who are taking glucocorticosteroids and have osteoporosis or DXA-defined osteopenia. Lehouck et al's helpful diagnostic and interventional algorithm for patients with COPD and low BMD advocates a more aggressive approach to its diagnosis and management.23
7 Gastro-oesophageal reflux disease
Symptoms of gastro-oesophageal reflux disease (GORD) occur in 30–60% of patients with COPD and increase in prevalence with severity of airflow limitation.6,38 Many episodes of reflux are asymptomatic and may only be detected by oesophageal manometry, so a high index of suspicion is warranted.39
The fundamental mechanism underlying GORD is transient relaxation of the lower oesophageal sphincter, thereby permitting movement of gastric contents into the oesophagus, larynx, and mouth when intra-abdominal pressure is high.6,38 People with COPD often have a low-lying diaphragm as a result of hyperinflation, coughing, and increased use of abdominal muscles for ventilation, all of which contribute to a raised intra-abdominal pressure predisposing to GORD. Overspilling of gastric contents into the airway can cause inflammation and increase the chances of an exacerbation. A history of heartburn or reflux is an independent predictor of frequent exacerbator status.6,40
Several options exist to treat GORD. There are no COPD-specific recommendations, so management should follow standard practice.6
As with many other chronic symptomatic conditions, depression is a common comorbidity in people with COPD. In the ECLIPSE study, about one-quarter of patients with COPD had depression compared with 12% of controls, and the prevalence of depression increased with increasing COPD severity, although scores were more closely related to health status and symptoms than to lung function.6,41 Depression scores also rise acutely during exacerbations, and people with frequent exacerbations have higher depression scores.
As depression in patients with COPD is under-recognised, screening questionnaires (e.g. the Hospital Anxiety and Depression Scale) may be useful in identifying those with comorbid depression.42 Pulmonary rehabilitation, antidepressants, and behavioural strategies may be beneficial but more work is needed in this area. Identifying patients with COPD who also have clinical depression and/or anxiety remains a challenge.
9 Lung cancer
Although smoking causes COPD and lung cancer, airway obstruction is more strongly associated with lung cancer than with smoking status or the degree of smoking.43,44
In patients with moderate to severe airway obstruction, the incidence of lung cancer is high among former and current smokers (6.8% vs 10.8%, respectively).44 Moreover, the risk of developing lung cancer is proportional to the severity of airway obstruction, with hazard ratios for developing lung cancer of 1.4–2.7 and 2.8–4.4, respectively, in patients with mild to moderate and severe COPD compared with smokers with normal lung function.44 Even small reductions in lung function in smokers are associated with a significant increase in the risk of lung cancer; this is less pronounced in men than women, as the risk of lung cancer is 3.5-fold higher for women than men with similar levels of FEV1.44
Clinicians should have a high index of suspicion for lung cancer, as even nonsurgical patients have good survival outcomes. Radiofrequency ablation offers an alternative in patients unfit for surgery.
10 Skeletal muscle dysfunction
Skeletal muscle dysfunction can affect exercise capacity and functional activity levels in people with COPD, thereby impacting upon their quality of life.6 Skeletal muscle weakness, as measured by quadriceps strength, is present in 32% of patients with COPD.6,45
Around one-quarter of individuals with GOLD stage I and II COPD have skeletal muscle dysfunction, increasing to 38% in patients with GOLD stage IV disease.6,45 There is a relationship between: quadriceps strength and fat-free mass index; Medical Research Council (MRC) dyspnoea score; BMI, airflow obstruction, dyspnoea and exercise capacity (BODE) index; and mortality.45,46
The probable pathophysiological causes of skeletal muscle weakness in COPD are likely to be many; they may include reduced activity leading to atrophy, the use of systemic glucocorticosteroids, inflammation, hypoxia, and oxidative stress. Also a change in the muscle fibres of people with COPD appears to result in reduced endurance.6
Skeletal muscle assessment is not common in routine clinical practice due to equipment and time constraints. Patients with COPD and suspected skeletal muscle weakness could be referred for pulmonary rehabilitation.6,45 Recent evidence suggests that neuromuscular stimulation of affected muscles may be a useful adjunct.47
- Franssen F, Rochester C. Comorbidities in patients with COPD and pulmonary rehabilitation: do they matter? Eur Respir Rev 2014; 23: 131–141.
- Vanfleteren L, Spruit M, Groenen M et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med 2013; 187 (7): 728–735.
- Martinez C, Mannino D, Divo M. Defining COPD-related comorbidities, 2004–2014. J COPD F 2014; 1 (1): 51–63.
- Barr R, Celli B, Mannino D et al. Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med 2009; 122 (4): 348–355.
- Patel. The impact of ischaemic heart disease on symptoms, health status, and exacerbations in patients with COPD. Chest 2012; 141 (4): 851–857.
- Patel A, Hurst J. Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art. Expert Rev Respir Med 2011; 5 (5): 647–662.
- Soriano J, Visick G, Muellerova H et al. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest 2005; 128 (4): 2099–2107.
- Agusti A, Calverley P, Celli B et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11: 122.
- Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005; 4: CD003566.
- Gottlieb S, McCarter R, Vogel R. Effect of betablockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998; 339 (8): 489–497.
- Rutten F, Zuithoff N, Hak E et al. β-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med 2010; 170 (10): 880–887.
- Vestbo J, Anderson W, Coxson H et al. Evaluation of COPD longitudinally to identify predictive surrogate end-points (ECLIPSE). Eur Respir J 2008; 31 (4): 869–873.
- Mascarenhas J, Lourenço P, Lopes R et al. Chronic obstructive pulmonary disease in heart failure. Prevalence, therapeutic and prognostic implications. Am Heart J 2008; 155 (3): 521–525.
- Abusaid G, Barbagelata A, Tuero E et al. Diastolic dysfunction and COPD exacerbation. Postgrad Med 2009; 121 (4): 76–81.
- Kessler R, Faller M, Weitzenblum E et al. 'Natural history' of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164 (2): 219–224.
- Incalzi R, Fuso L, De Rosa M et al. Comorbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J 1997; 10 (12): 2794–2800.
- Arcasoy S, Christie J, Ferrari V et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167 (5): 735–740.
- Mapel D, Dedrick D, Davis K. Trends and cardiovascular co-morbidities of COPD patients in the Veterans Administration Medical System, 1991–1999. COPD 2005; 2 (1): 35–41.
- Steer J, Gibson J, Bourke S. The DECAF Score: predicting hospital mortality in exacerbations of chronic obstructive pulmonary disease. Thorax 2012; 67 (11): 970–976.
- Feary J, Rodrigues L, Smith C et al. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke, a comprehensive analysis using data from primary care. Thorax 2010; 65 (11): 956–962.
- Donaldson G, Hurst J, Smith C et al. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010; 137 (5): 1091–1097.
- Graat-Verboom L, Wouters E, Smeenk F et al. Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J 2009; 34 (1): 209–218.
- Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and osteoporosis. Chest 2011; 139 (3): 648–657.
- Ohara, T, Hirai, T, Muro, S et al. Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD. Chest 2008; 134: 1244–1249.
- Sin D, Man J, Man S. The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med 2003; 114 (1): 10–14.
- Sabit R, Bolton C, Edwards P et al. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175: 1259–1265.
- Lindsay R, Silverman S, Cooper C et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001; 285 (3): 320–323.
- Siris E, Chen Y, Abbott T et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 2004; 164 (10): 1108–1112.
- Myers A, Robinson E, Van Natta M et al. Hip fractures among the elderly: factors associated with in-hospital mortality. Am J Epidemiol 1991; 134 (10): 1128–1137.
- Dam T, Harrison S, Fink H et al. Bone mineral density and fractures in older men with chronic obstructive pulmonary disease or asthma. Osteoporos Int 2009; 21 (8): 1341–1349.
- Kanis J, Johansson H, Oden A et al. A metaanalysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19 (6): 893–899.
- van Staa T, Leufkens H, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002; 13 (10): 777–787.
- McEvoy C, Ensrud K, Bender E et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 704–709.
- Walsh L, Wong C, Oborne J et al. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 2001; 56: 279–284.
- Lim L, Hoeksema L, Sherin K, ACPM Prevention Practice Committee. Screening for osteoporosis in the adult U.S. population. ACPM position statement on preventive practice. Am J Prev Med 2009; 36 (4): 366–375.
- Kanis J, McCloskey E, Johansson H et al. Case finding for the management of osteoporosis with FRAX—assessment and intervention thresholds for the UK. Osteoporos Int 2008; 19 (10): 1395–1408.
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- Seymour J, Spruit M, Hopkinson N et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 2010; 36 (1): 81–88.
- Swallow E, Reyes D, Hopkinson N. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 2007; 62: 115–120.
- Maddocks M, Nolan C, Man W et al. Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: a randomised double-blind, placebo-controlled trial. Lancet Respir Med 2016; 4: 27–36. G